U.S. Pat. No. 4,525,358 discloses the preparation of aliphatic carboxylic acids substituted with 1-alkoxy-4-alkylpiperazines having the formula ##STR3##
where Y is an ester, hydroxy or amino group, X and X' are independently hydrogen, halo, linear or branched lower alkoxy or trifluoromethyl and m and n are the integers 1 or 2. A number of reaction routes for the preparation of these acetic acid derivatives are shown, e.g., the reaction of 1-(diphenylmethyl)-piperazine with an omega haloacetamide followed by hydrolysis, the reaction of the alkali metal salt of an omega-[4(diphenylmethyl)-1-piperazinyl]alkanol with a 2-haloacetamide followed by hydrolysis, etc.
UK Patent Application 2,225,321, published on May 30, 1990 discloses that 2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid, i.e., the compound shown above where Y is hydroxy, X is hydrogen, X' is chloro and m and n are the integer 1, may be prepared by hydrolyzing 2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetonitrile with base or with acid. The nitrile is prepared by reaction of racemic 1-[(4-chlorophenyl)phenylmethyl]-piperazine with 2-chloroethoxyacetonitrile.
UK Patent Application 2,225,320, published May 30, 1990 discloses the preparation of 2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid by the reaction of 2-[-4-[(4-chlorophenyl)-phenylmethyl]-piperazinyl]1-ethan-1-ol with an alkali metal haloacetate in the presence of an alkali metal alcoholate followed by removal of the alkali metal salt with acid to form the free acid or its acid salt.
In a reaction that uses one of the same starting materials disclosed in the UK '320 application, Polish patent PL 163415 B1 published on Apr. 21, 1992 discloses preparation of 2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid by the reaction of 2-[4-[(4-chlorophenyl)-phenylmethyl]-piperazinyl] 1-ethan-1-ol with chloroacetic acid, in a two phase system that is an organic phase (the substrate and an inert solvent) and an inorganic phase (the hydroxide of an alkali metal in water). A yield of 67% was reported.
Japanese patent application JP 04112852 A2 , published Apr. 14, 1992 discloses a method for the preparation of haloalkoxy acetic acid derivatives having the formula EQU X--(CH.sub.2).sub.m --O--CH(R)--CO(O)R'
where X is a halide, m is a number between 2 and 7, R is hydrogen or lower alkyl and R' is hydrogen or an ester group. This reference further discloses that the above compound is a useful intermediate for the preparation of Cetirizine [(2-(4-(4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy acetic acid. Details of such preparation are not, however, shown in this reference.
It would be desirable to have synthetic routes for the preparation of the physiologically active compounds similar to those disclosed in U.S. Pat. No. 4,525,358 that result in higher yields or higher purity products.